When cardiac muscle is completely deprived of O2 because of occlusion of a coronary vessel (i.e., stopped-flow ischemia), contractions quickly cease (within 30 seconds). This is not due to depletion of either ATP or creatine phosphate because these levels decline more slowly. Even after 10 minutes of stopped-flow ischemia, when creatine phosphate levels are near zero and only 20% of the ATP remains, reperfusion can restore these energy stores, as well as contractile ability. However, prolonging the stopped-flow ischemia for 20 minutes results in further drops in ATP, so that reperfusion has considerably less effect, with only limited restoration of ATP and creatine phosphate levels or contractile activity.
Exercise such as endurance running can increase the size of the heart as a result of hypertrophy of individual cardiac muscle cells. Concomitant with this enlarged so-called athlete’s heart is improved cardiac performance, as assessed by an increase in stroke volume, increased oxygen consumption, and preserved relaxation. Thus the athlete’s heart represents an example of “physiological hypertrophy,” with beneficial contractile effects.
In contrast, if exposed to chronic pressure overload, the heart may undergo either concentric left ventricular hypertrophy or dilated left ventricular hypertrophy, which causes impairment of function. Details regarding the morphological, functional, and mechanistic differences between these various types of hypertrophy can be found elsewhere in this textbook (see
Chapter 18).
Concentric hypertrophy is characterized by thickening of the left ventricular wall and represents a compensatory hypertrophy to the increased load. Dilated hypertrophy is characterized by increased ventricular volume (end-diastolic volume). Both concentric/compensatory left ventricular hypertrophy and dilated left ventricular hypertrophy have been shown to exhibit decreased contractile response to β-adrenergic stimulation, which limits the contractile reserve. In dilated left ventricular hypertrophy, normal •Fig. 13.6 Stretchingoftheheartincreasestheforceofcontraction(A). ThisisattributabletobothanincreaseinthemaximalforceofcontractionandanincreaseinthesensitivityofcontractiontoCa++ (B). ItreflectsanintrinsicregulatoryprocessreferredtoastheFrank-Starling law of the heart. (B,RedrawnfromDobeshD,KonhilasJ,deTombeP.Cooperativeactivationincardiacmuscle:impactofsarcomerelength.Am J Physiol Heart Circ Physiol. 2002;282:H1055-H1062.) contractile function, along with the Frank-Starling response, may also be impaired.
The cellular and molecular mechanisms underlying the development of cardiac hypertrophy are not clear, although an elevation in intracellular [Ca++] has been implicated.
The link or links between cardiac hypertrophy, decreased cardiac performance, and impaired β-adrenergic response during chronic pressure overload are unclear. Decreased cardiac performance has been attributed to dysregulation of intracellular [Ca++]. Alterations in the level, activity, and phosphorylation status of a variety of proteins, including L-type calcium channels, phospholamban, SERCA, and RYR, have all been implicated in the Ca++ dysregulation associated with a failing heart (pathological hypertrophy).
A microRNA (miR-222) has been shown to be important for cardiac growth in response to exercise. It also appeared to inhibit maladaptive remodeling of the heart after ischemia/ reperfusion injury.